Background: People living with HIV/AIDS smoke at nearly three times the rate of the general population. In our view, shared by others in the field, the single greatest health behavior change that could improve cardiovascular morbidity and associated mortality is to assist people living with HIV/AIDS who smoke to quit. Although many interventions are effective in helping general population smokers quit, research examining outcomes of smoking cessation treatments for individuals with HIV is limited. Thus establishing the efficacy of interventions for smoking cessation for individuals with HIV is of critical importance and is directly responsive to the RFA which specifically requests proposals to test strategies to optimize smoking cessation in HIV populations.? Approach: Our proposed study will use a factorial design to evaluate the most promising behavioral and pharmacologic treatments aimed at achieving maximal efficacy for smoking cessation among people living with HIV/AIDS who smoke. Specifically, we propose to randomize 300 participants to one of the following 4 conditions: (1) varenicline + Positively Smoke Free (an 8 session smoking cessation intervention tailored for PLWH); (2) varenicline + Standard of Care (brief advice to quit); (3) Placebo + Positively Smoke Free; and (4) Placebo + Standard of Care. Given the factorial nature of the design, we will be able to assess the main effect of varenicline vs. Placebo, Positively Smoke Free vs. Standard of Care, and the interaction of those two treatments (i.e., does the addition of varenicline significantly increase the effect of Positively Smoke Free?). We chose to use a factorial design as it is a highly efficient method of assessing multiple treatments in a single trial with the possibility of saving both time and resources. All participants will be assessed at baseline, 12 weeks and 24 weeks with the main outcome being 7-day abstinence (defined as self-reported no smoking in the past 7 days + CO<10 ppm). We will then follow-up all participants at 6 months post study conclusion to assess continued abstinence as well as changes in cardiovascular risk. The sizeable cohort and prospective design will also permit us to evaluate the effects of tobacco use, treatment, and cessation on a panel of soluble biomarkers of inflammation that are likely contributors to cardiac morbidity and mortality in PLWH. Implications: Results of this study will provide crucial, real world evidence of the best way for healthcare providers to help smokers living with HIV/AIDS quit smoking with the ultimate goal of improving longevity by lowering risk of mortality, especially cardiac-related mortality.